Introduction

Lung Cancer (LC) is the leading cause of cancer deaths in developed countries, and represents a very significant healthcare issue². Globally, LC accounts for 13% of all new tumours diagnosed each year³. It affects around 26,700 Spanish people per year⁴ with an age-adjusted incidence rate of 76.8/100,000 in men and 15.7/100,000 in women, when using the European standard population as reference⁵.

Prevalence is low due to the poor prognosis of the disease and the low rates of survival at 1 and 5 years⁶. It is estimated that the prevalence at 5 years of Spanish patients with LC is 7.0% for men and 2.1% for women⁷. Non small cell lung cancer (NSCLC) represents around 80% of LC cases, and has a high impact on the health-related quality of life (HRQoL) of patients and their relatives or caregivers⁸. The presence of symptoms such as dyspnoea, fatigue, coughing, insomnia, loss of appetite and pain, as well as the disease evolution, the presence of metastasis, and the adverse effects of antineoplastic treatments, will have a negative impact on the HRQoL of patients9.

Current treatment for advanced or metastatic NSCLC includes different drugs, depending on baseline characteristics of patients. NSCLC must be histological classified (adenocarcinoma, large cell carcinoma or squamous cell carcinoma). After the failure of first line chemotherapy, the treatment will have a palliative objective: to increase survival and quality of life of patients. The drugs approved for second line treatment of patients with no specific mutations are: monotherapy with docetaxel, erlotinib and pemetrexed.

Different studies with new biologic agents have tried to improve the poor results obtained by these drugs as second line. The outcomes of three molecules with impact on overall survival (OS) have been recently publi- shed: nintedanib and ramucirumab, both in combination with docetaxel, and nivolumab.

Nintedanib (Vargatef®; Lab. Boehringer Ingelheim International) has been approved by the European Medicines Agency (EMA)¹⁰ and the Spanish Agency of Medicines and Healthcare Products (AEMPS)11, in combination with docetaxel, for the treatment of adult patients with locally advanced, metastatic or locally recurrent NSCLC, with adenocarcinoma histology, after first-line chemotherapy.

Nintedanib is a tumour angiogenesis inhibitor which acts as a triple angiokinase inhibitor blocking vascular endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors (PDGFR  and ß) and fibroblast growth factor receptors (FGFR 1-3) kinase activity.

Efficacy

A randomized controlled trial has been carried out for the indication evaluated: the LUME-Lung 1 – 1199.13 study; its outcomes have been detailed in two articles: Reck et al¹² published the primary efficacy and safety outcomes, while Novello et al¹³ published the quality of life outcomes. LUME-Lung 1 was a international Phase III, multicentre, randomised, double-blind and placebo-controlled study which included adults patients with stage IIIB/IV recurrent NSCLC progressing after failure of first-line chemotherapy, stratified by ECOG performance status, previous bevacizumab treatment, histology (squamous/non-squamous), and presence of brain metastases. 1,314 patients were randomized to receive docetaxel 75 mg/m2 by intravenous infusion on day 1 plus either nintedanib 200 mg orally twice daily or matching placebo on days 2–21, every 3 weeks until unacceptable adverse events or disease progression. Eligibility criteria included Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and at least one target lesion measurable according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. Patients with active brain metastases, previous treatment with docetaxel or VEGFR inhibitors with the exception of bevacizumab or a recent history (<3 months) of clinically significant haemoptysis or a major thrombotic or clinically relevant major bleeding event in the past 6 months were also excluded from the study were excluded.

The primary endpoint was progression free survival (PFS) defined as time from randomization to progression or death according to the modified RECIST 1.0 criteria, by central independent review. Overall survival (OS) was a predefined, key secondary outcome and was assessed hierarchically: first in adenocarcinoma patients with early progression, followed by all adenocarcinoma patients and then in the overall population. Other secondary endpoints were: quality of life, PFS assessed by investigator, objective response rate and disease control rate. Table 1 shows the results of LUME-Lung 1.

The approved indication was supported by another phase III clinical trial (1199.14; LUME-Lung 2). In this trial nintedanib was evaluated in combination with pemetrexed but it was halted based on the futility analysis performed by an independent data monitoring committee and the study was unblinded. Trial 1199.¹⁴ did not pass the futility analysis, which indicated that the endpoint PFS based on investigator assessment would likely not be met. (Non-published clinical trial, information extracted from the EPAR report¹⁰).

Safety

Based on the clinical trial experience the most frequent adverse events (AEs) of the nintedanib plus docetaxel combination were: neutropenia (including febrile neutropenia), decreased appetite, electrolyte imbalance, peripheral neuropathy, bleeding, diarrhoea, nausea, vomiting, liver enzyme elevations (AST/ALT), alkaline phosphatase increased, mucositis, and rash. Nintedanib did not increase the haematological toxicity of docetaxel, though it caused a higher rate of diarrhoea (42.3% vs. 21.8%), increases in ALT (28.5% vs. 8.4%), nausea (24.2% vs. 18.0%), increases in AST (22.5% vs. 6.6%), decreased appetite (22.2% vs. 15.6%) and vomiting (16.9% vs. 9.3%). Most of these adverse events were manageable with supportive treatment or dose reduction; however, this did not cause a detrimental effect on patient`s quality of life.

The analysis of AEs of special interest associated with antiangiogenic agents, such as hypertension, bleeding or gastrointestinal perforation, were similar in both treatment arms.

There was a higher incidence of AEs leading to death in the nintedanib arm. Time-to-death was similar for these patients when comparing the two treatment arms. Thus, it was that the add-on of nintedanib did not lead to earlier AEs leading to deaths. In the overall population in study LUME-Lung 1 the majority of AEs leading to death were due progression disease (PD). In the placebo arm 25 AEs leading to death were not attributed to PD compared to 35 in the nintedanib arm. The most common were: sepsis, pneumonia, respiratory failure and pulmonary embolism.

The safety of nintedanib in children aged 0-18 years has not been established and no data are available. The safety of nintedanib has not been studied in patients with severe renal or liver impairment

Economic area

On December, 1st, 2015, the notified price for nintedanib (Vargatef®) 100 mg in a package with 120 capsules was 2,403.85€ (List Price).

The economic evaluation has been performed with the notified price (Scenario 1, Tables 2 and 3), and a sensitivity analysis has been performed, because its price will be probably lower in the Public Health System; therefore, we have applied a 25% discount rate, determining the price per capsule 5€ cheaper than the notified price (Scenario 2, Tables 2 and 4)b.

According to the results of LUME-Lung 1, with the addition of nintedanib to docetaxel the estimated incre- mental cost effectiveness ratio (ICER) of PFS in overall population would be 134,274.47€ (notified price) while applying a sensitivity analysis with a 25% discount, its ICER could be 106,340.33€.

In the adenocarcinoma population the ICER could be 40,886.14€/LYG (life of year gained) with de addition of nintedanib to docetaxel, while applying a sensitivity analysis with a 25% discount, the ICER would be lower: 32,364.05€/LYG.

In terms of the budget impact at national level, we considered that around 26,7¹⁵ lung cancer cases were diagnosed in 2012th year in Spain¹⁴. 55% of the cases diagnosed were NSCLC in Stage IIIB and IV, candidate to non-surgical treatment (14,693)¹⁵. In terms of histology, 38% of these patients would have adenocarcinoma (5,583)^16,17. According to the study by Leighl¹⁸, mentioned in the article that describes the outcomes of the pivotal study, approximately 30% are candidate to receiving second line treatment. This represents approximately 1,675 patients candidate to receiving second line treatment per year.

If all these patients were treated with the nintedanib plus docetaxel combination, the budget impact at national level would be between 13 and 10 million of Euros, depending on the price considered: whether the notified price or price with 25% discount, respectively.

Probably, not all NSCLC patients with adenocarcinoma in second line will be candidate to receive chemotherapy with docetaxel; therefore, this budget impact could be even lower.

Additional Considerations

Nintedanib is a triple angiokinase inhibitor that has been evaluated in two phase III clinical trials for NS- CLC: LUME-Lung 1 and LUME-Lung 2. The LUME-Lung 1 trial provided evidence of a difference in PFS in favour of nintedanib that was statistically significant and clinically relevant in the overall population with NSCLC. The efficacy outcomes in the population with adeno- carcinoma state a significant effect in OS. Both the LUME-Lung 1 and the LUME-Lung 2 studies support the beneficial effect of nintedanib on the population with adenocarcinoma.

The LUME-Lung 2 clinical trial for nintedanib plus pemetrexed vs. placebo plus pemetrexed generated the hypothesis that patients who progressed in the first 9 months after initiating their first line of chemotherapy or patients with adenocarcinoma were the most benefited from treatment with nintedanib. This generated a change in the statistical plan of the LUME-Lung 1 trial, through an amendment before closing the database, which did not affect the initial analysis of PFS but had an impact on the final OS analysis, replacing it by a rank analysis. The LUME-Lung 2 had to be prematurely halted, because the expected outcomes were not achieved in a futility analysis, though a subsequent data review showed a tendency in favour of the experimental arm¹⁰.

In LUME-Lung 1, at the time of final analysis (median follow-up of 31.7months), nintedanib plus docetaxel significantly prolonged OS by 3 months in adenocarcinoma patients with early progression and by 2.3 months in all adenocarcinoma patients relative to placebo plus docetaxel. No significant between-group difference in OS was seen in the overall population. This outcome shows a statistically significant effect; it is clinically small, though it can be considered relevant within the context in which it has been evaluated. The hazard ratio (HR) for OS in the adenocarcinoma population was 0.83 (CI 95% 0.7-0.99); p=0.0359. In patients with adenocarcinoma and progression < 9 months after the initiation of first line treatment, outcomes were slightly better, because the HR for OS was 0.75 (CI 95% 0.6-0.92); p=0.0073, with a difference of 3 months in favour of the nintedanib arm, though it is not known whether patient characteristics have been well balanced in this group.

In the analysis of OS by adenocarcinoma patient groups ranked according to their baseline characteristics, a different tendency is shown in OS between patients with <9 months from the initiation of first line treatment and without brain metastasis, however these differences are not statistically significant.

The LUME-Lung 1 study is a well-designed clinical trial, with a low risk of bias. It was conducted as a blind clinical trial until its completion. The baseline characteristics of patients (including the adenocarcinoma population) were well balanced. Comparison with docetaxel was considered adequate.

Nintedanib is an oral drug. The recommended dose of nintedanib is 200 mg twice daily administered approximately 12 hours apart, on days 2 to 21 of a standard 21 day docetaxel treatment cycle. Nintedanib do not improve patient convenience because it does not prevent patients from attending a chemotherapy unit to receive IV treatment.

Currently, the drugs approved for second line treatment in patients with no specific mutations are: doceta- xel, erlotinib and pemetrexed as monotherapy.

Different studies with new biologic agents have tried to improve the poor results obtained by these drugs as second line treatment. In this context, three molecules have appeared with impact on OS: nintedanib and ramucirumab, both in combination with docetaxel, and nivolumab as monotherapy.

The Spanish therapeutic positioning report19 has been published and its conclusions are that those patients candidate to receive second line treatment with nintedanib in combination with docetaxel would be those for whom the status of the activating mutation EGFR is unknown or negative, after a first line of chemotherapy, as long as the first line has not included docetaxel or VEGF inhibitors, except for bevacizumab.

Regarding the economic evaluation, and considering that in Spain no ICER value has been officially established, it is suggested to take as reference the value most frequently used in Spain, according to bibliography: 30.000€/QALY (quality of life-adjusted life year). Taking into account the notified price, the efficiency threshold is slightly exceeded. Through the discount assessed in the sensitivity analysis, the result achieved is very close to the value considered efficient.

Conclusion, Therapeutic Positioning and Conditions of Use

In view of the efficacy and safety results, the proposed positioning is considered Category D-1: It is included in the Formulary with specific recommendations: Use for adult patients with the following characteristics:

• Metastatic or locally recurrent NSCLC with adenocarcinoma histology after first line chemotherapy, and with progression < 9 months since first line treatment initiation.

• Life expectancy ≥3 months.

• Good Performance Status. ECOG 0-1.

• The status of the activating mutation EGFR is not known or negative, and there is no ALK translocation.

The following will not be considered adequate for treatment with nintedanib:

• Patients who have received more than one previous line of treatment.

• Patients who have received previous treatment with VEGFR, except for bevacizumab.

• Patients who present active brain metastasis.

• Patients who present clinically relevant cardiovascular disease (uncontrolled hypertension, unstable angina, previous history of myocardial infarction within the last 6 months, heart failure, relevant arrhythmia, and any other considered relevant).

• Patients who have received previous treatment with docetaxel.

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Additional information

Conflict of Interests: The authors declare no conflict of interest.